Non-alcoholic fatty liver disease (NAFLD) is complicated disease and increasing worldwide. Previously, many studies of NALFD prevalences have used alanine aminotransferase (ALT) of > 40 U/L to define NAFLD, although that is too high to be reliable among adolescents.
Trang 1R E S E A R C H A R T I C L E Open Access
Normal serum alanine aminotransferase
and non-alcoholic fatty liver disease among
Korean adolescents: a cross-sectional study
Yunkoo Kang, Sowon Park, Seung Kim and Hong Koh*
Abstract
Background: Non-alcoholic fatty liver disease (NAFLD) is complicated disease and increasing worldwide Previously, many studies of NALFD prevalences have used alanine aminotransferase (ALT) of > 40 U/L to define NAFLD, although that is too high to be reliable among adolescents This study aimed to define the upper normal limit of ALT among Korean adolescents, and use it to estimate the prevalence of NAFLD, based on data from the Korea National Health and Nutrition Examination Survey (KNHANES)
criteria for adolescents were used to exclude participants with metabolic syndrome components Furthermore, participants who previously had diseases related to low HDL levels, high TG levels, diabetes, or very low/high body mass index and hepatitis B were excluded The 95th percentiles level of ALT from healthy participants
elevated ALT levels (95th percentile)
Results: The upper normal ALT were 24.1 U/L for boys and 17.7 U/L for girls Based on these values, the estimated prevalences of NAFLD in 2015 were 8.9% among adolescents
Conclusion: Defining the upper normal limit of ALT can be adjusted for each sex and ethnics in the general population ALT laboratory thresholds used for children should be re-examined The physicians should be aware not to underdiagnose NAFLD patient even ALT level is < 40 U/L
Keywords: Non-alcoholic fatty liver disease, Alanine aminotransferase, Korea, Upper normal limit
Background
General and specific background
The prevalence of non-alcoholic fatty liver disease (NAFLD)
is increasing worldwide [1] Therefore, it is necessary for
obese adolescents to be actively examined for NAFLD And
symptoms and clinical signs, laboratory and radiological
im-aging test, and liver biopsy is needed to make diagnosis
finally as NAFLD [2,3] But in general population, it is not
possible to perform all diagnostic procedures for each
people Therefore, Alanine aminotransferase (ALT) is used
to find prevalence in general populations ALT is an enzyme that is found in the cytosol of hepatocytes, and blood levels
of ALT increase after liver injury [4] Thus, blood testing for ALT is used globally as a minimally invasive and inexpen-sive tool for detecting chronic liver diseases, such as non-alcoholic fatty liver disease (NAFLD) [1]
Debating issue
However, the reference ranges for normal ALT vary widely across different laboratories and populations [1] Among adults, the upper normal limit of ALT was de-rived from healthy Italian blood donors, with values of
* Correspondence: khong@yuhs.ac
Department of Pediatrics, Severance Children ’s Hospital, Severance Pediatric
Liver Disease Research Group, Yonsei University College of Medicine, 50-1
Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
© The Author(s) 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver
Trang 230 U/L for men and 19 U/L for women [5] Among
American adolescents, the upper normal limit of ALT
was estimated by the National Health and Nutrition
Examination Survey to be 25.8 U/L for boys and 22.1 U/
L for girls [6,7]
Specific purpose of this study
Nevertheless, population differences indicate that these
values may not be the same among Korean adolescents
However, the method used to define NAFLD in this
study is only tools to estimated NAFLD in public
popu-lations, so this result cannot directly be used in clinic
But result of this study will give clues to evaluate and
manage NAFLD in clinic Therefore, the present study
aimed to estimate the upper normal limits of ALT
among Korean adolescents, as well as the prevalences of
NAFLD based on those values
Methods
Database
The present study evaluated data from the 2010–2015
Korea National Health and Nutrition Examination
Survey (KNHANES) These annual cross-sectional
surveys are performed using multi-stage probability
samples that are representative of the general Korean
population The data of KNHANES surveys are
avail-able at http://knhanes.cdc.go.kr/
Study sample
During 2010–2015, 48,482 individuals participated in the
KNHANES The present study included participants
who were 10–18 years old, but excluded participants
with missing data and metabolic syndrome components, based on the International Diabetes Federation consen-sus definition (www.idf.org) Furthermore, 10–15-year old participants were excluded if they had a waist circumference of≥90th percentile for sex and age, trigly-ceride (TG) levels of ≥150 mg/dL, high density lipopro-tein (HDL) levels of < 40 mg/dL, systolic blood pressure (SBP) of ≥130 mmHg, diastolic blood pressure (DBP) of
≥85 mmHg, and glucose levels of ≥100 mg/dL More-over, participants who were 16–18-years-old were excluded if they had a waist circumference of≥90 cm or HDL levels of < 40 mg/dL (boys), a waist circumference
of≥80 cm or HDL levels of < 50 mg/dL (girls), TG levels
and glucose levels of ≥100 mg/dL Finally, we excluded participants who previously had diseases related to low HDL levels, high TG levels, diabetes, or very low/high body mass index (BMI, <5th percentile or > 85th per-centile) [8] Furthermore, participants who had hepatitis
B infection were excluded Thus, 1785 healthy partici-pants (916 boys and 869 girls) were included in the ana-lysis to determine the upper normal limit of ALT For the present study, NAFLD was defined as being over-weight (≥85th percentile of BMI) plus having elevated ALT (≥95th percentile, 24.1 U/L for boys and 17.7 U/L for girls) A total of 4149 participants (2226 boys and
1923 girls) were included in the analyses to estimate the prevalence of NAFLD (Figure1) [9]
Statistical analysis
All statistical analyses were performed using SPSS soft-ware (version 23.0; IBM Inc., Armonk, NY) Categorical
Fig 1 Flow chart for participant selection (916 boys, 869 girls)
Trang 3data were collected for healthy participants (without
meta-bolic syndrome components), and continuous laboratory
and anthropometry data were expressed as mean ±
stand-ard error The 95th percentiles for ALT were estimated
for each sex using weighted analysis, and those values
were used to estimate the prevalences of NAFLD among
adolescents who participated in KNHANES and had
avail-able BMI and ALT data
Results
Characteristics of the healthy participants
The characteristics of the 1785 healthy participants (916
boys and 869 girls) are shown in Table1 All characteristics
appeared to be within the normal ranges, and the mean
ALT levels were 14.2 U/L for boys and 10.9 U/L for girls
The 95th percentiles for ALT among healthy participants
were 24.1 U/L for boys and 17.7 U/L for girls (Figure2a)
Prevalence of elevated ALT among Korean adolescents
A total of 4149 KNHANES participants had available
ALT and BMI data Among all participants during 2010–
2015, the estimated prevalence of elevated ALT levels
was 10.9% (95% confidence interval [CI]: 9.8–12.1%)
During 2015, the overall estimated prevalence of
ele-vated ALT levels was 13.7% (95% CI: 11.0–15.5%) In
addition, the estimated prevalences of elevated ALT
levels during 2015 were 14.9% (95% CI: 11.0–19.8%) for
boys and 12.3% (95% CI: 8.6–17.3%) for girls (Figure2b)
Prevalence of NAFLD among Korean adolescents
The prevalence of NAFLD was estimated using the 95th
percentile values for ALT (24.1 U/L for boys and 17.7 U/
L for girls) plus the age- and sex-specific 85th percentile values for BMI During 2015, the overall prevalence of NAFLD was 8.9% (95% CI: 6.7–11.6%), with prevalences
of 10.8% (95% CI: 7.7–15.0%) among boys and 6.6% (95% CI: 4.0–10.9%) among girls (Figure3)
Discussion The present study evaluated data from the general popu-lation of healthy Korean adolescents to estimate the upper normal limit of ALT The results indicate that the upper limits (95th percentiles) for estimating the preva-lence of NAFLD in this population were 24.1 U/L for boys and 17.7 U/L for girls These values are similar to, albeit lower than, the values among American adoles-cents (25.8 U/L for boys, 22.1 U/L for girls) [6]
The present study used the upper normal limit of ALT to estimate the prevalence of NAFLD, which re-vealed values of 10.8% among boys and 6.6% among girls in 2015 In contrast, use of the previous standard values (30 U/L for boys and 19 U/L for girls) generated estimated NAFLD prevalences of 6.7% among Korean boys and 5.1% among Korean girls in 2015 [10] [5, 11] Thus, the prevalence of NAFLD in this population appears to be unexpectedly high, and we recommend aggressive management for patients who may have un-detected NAFLD based on the previous standard ALT values
The prevalence of NAFLD (elevated ALT levels (>
30 U/L)) was 3.6% in boys and 2.8% in girls from 1594 adolescents aged 10 to 19 years using the 1998
children found out to be 9.03% with ALT thresholds > 25.8 U/L for boys > 22.1 U/L for girls using China Health and Nutrition Surveys [13] Although there is a lack of uniformity in the data, but similar results were obtained with studies conducted in China from our study Emma et al pooled prevalence of NAFLD as 7.6% (95%CI: 5.5 to 10.3%) using meta-analysis and showed that it did not differ by geographical region among chil-dren and adolescents [14, 15] Even with heterogenicity
of defining NALFD across studies, it seems that the prevalence of NAFLD increase with time and has glo-bally similar prevalence
This study had some important limitations First, we used elevated ALT plus elevated BMI as criteria to diag-nose NAFLD Some NAFLD patients may have normal ALT levels and it does not parallelly match the histo-logical severity of NAFLD in children [16] So, in order
to diagnose NALFD, imaging investigations or histology confirmation should be included However, we have not been able to confirm NAFLD using imaging investiga-tion in this cohort study as it has not been used in every cycle of KNHANES Therefore, it could not be included
in the criteria of NAFLD in this study However, ALT
Table 1 The characteristics of healthy KNHANES participants
during 2010–2015
Cholesterol(mg/dl) 158.80 ± 0.74 152.82 ± 1.01 164.79 ± 1.06
Data are presented as mean ± standard error
SBP Systolic blood pressure, DBP Diastolic blood pressure, BMI Body mass
index, HDL High-density lipoprotein, TG Triglycerides, AST Aspartate
aminotransferase, ALT Alanine aminotransferase
Trang 4has been recommended as a screening tool for NAFLD
and has previously been used for population-based
epi-demiological studies [7, 8, 17] Furthermore, the upper
normal limits of ALT (24.1 U/L for boys and 17.7 U/L
for girls) should be validated using liver biopsies [7,18]
Second, the KNHANES data do not include information
regarding the use of hepatotoxic medication Third,
although ours is the most recent study to estimate the
sex-specific upper normal limits of ALT among Korean
adolescents, additional criteria should be considered
when using ALT levels to estimate the prevalences of
other chronic liver diseases in Korea As we mentioned
at the beginning, NAFLD should be diagnosed using liver biopsy or imaging studies So, results from present study cannot directly be used in clinic level
However, even with these limitation, this is first study
to define upper normal ALT level of adolescents by using KHANES data And according to our data, preva-lences of adolescents NAFLD in Korea might be more serious than we used to think As the result of this study shows normal value of ALT can varies by some circum-stances, ALT laboratory thresholds used for children should be re-examined The physicians should be aware not to underdiagnose NAFLD patient when ALT level is
Fig 2 Trends in the 95th percentiles for alanine aminotransferase (a) and the prevalence of participants with elevated alanine aminotransferase (>95th percentile) (b)
Fig 3 The estimated prevalence of non-alcoholic fatty liver disease among Korean adolescents
Trang 5in normal value we used to use in clinic However, the
defining NAFLD (BMI≥ 85th percentile plus elevated
ALT) used in the study is only tools to estimate NAFLD
in public populations, so this upper normal ALT results
cannot directly be used in clinic We hope these results
can give clues that ALT level can be adjusted for each
sex and ethnics And ALT could be more useful tool to
determine who may need more detailed medical
exami-nations for NAFLD if ALT is adjusted specific for each
ethnics and sex
Conclusions
The upper normal level of ALT in Korea were 24.1 U/L
for boys and 17.7 U/L for girls in our study And based on
the weighting of the KNHANES design, our estimates
in-dicate that NAFLD may be present in year 2015,
approxi-mately 282,981 adolescent boys and 159,154 adolescent
girls Thus, additional care is needed to identify Korean
adolescents with undetected NAFLD and its
complica-tions And further study is needed for evaluating
sensitiv-ity and specificsensitiv-ity of upper normal level of ALT from this
study
Abbreviations
BMI: Body mass index; DBP: Diastolic blood pressure; HDL: High density
lipoprotein; KNHANES: Korea National Health and Nutrition Examination
Survey; NAFLD: Non-alcoholic fatty liver disease; SBP: Systolic blood pressure;
TG: Triglyceride
Availability of data and materials
The all raw data of survey is available http://knhanes.cdc.go.kr / The datasets
during and/or analyzed during the current study available from the corresponding
author on reasonable request.
Authors ’ contributions
YK and HK conceived and led the design of the study, analyses, and drafting
of the article YK wrote the first draft of the paper YK, SP, SK, and HK
contributed to the discussion of the results, revisions, and approval of the
manuscript YK conducted the extraction of data and data analysis All
authors read and approved the final manuscript.
Ethics approval and consent to participate
The KNHANES surveys ( http://knhanes.cdc.go.kr /) are approved by the
Korean Center for Disease Control (2010-02CON-21-C, 2011-02CON-06-C,
2012-01EXP-01-2C, 2013-07CON-03-4C, 2013-122EXP-03-5C, and 2015
–01-02-6C), and all participants provide written informed consent.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Received: 9 November 2017 Accepted: 28 June 2018
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